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Recent Patents on Anti-Cancer Drug Discovery

Editor-in-Chief

ISSN (Print): 1574-8928
ISSN (Online): 2212-3970

Review Article

Chebulinic Acid: An Incipient Anticancer Agent

Author(s): Aashima, Mehak Rathi, Shilpi, Akash, Kamaljeet Kaur, Priyanka Kriplani* and Kumar Guarve

Volume 19, Issue 3, 2024

Published on: 11 September, 2023

Page: [298 - 307] Pages: 10

DOI: 10.2174/1574892819666230821110429

Price: $65

Abstract

Background: Terminalia chebula (T. chebula) comprising chebulinic acid as its principle active constituent is used to cure various diseases. T. chebula and chebulinic acid are used as antimicrobial, antioxidant, antidiabetic, anti-inflammatory, hepatoprotective, antimutagenic, radioprotective, cardioprotective, antiproliferative, antiarthritic, anticaries, and so on.

Objective: The objective of this current study is to give an overview of the recent literature and patents of T. chebula and chebulinic acid including methods of its isolation/extraction and their application in the prevention of various cancers and other diseases.

Methods: Present research and patents highlighting the anti-cancer potential of T. chebula and chebulinic acid have been studied and discussed keeping in view the scientific novelty and impact.

Results: Both T. chebula and chebulinic acid are currently being explored for their anticancer potential in vitro and in vivo. They are either incorporated alone or in combination with other plants or drugs to show their activity and many clinical trials are also going on various potentials of the plant and chebulinic acid. Novel extraction techniques are also explored and patented. Efforts are being made to improve the bioavailability by developing Novel herbal drug delivery systems of the plant extract or chebulinic acid itself.

Conclusion: Anti-cancer potential of T. chebula and chebulinic acid may be well established by promising clinical trials and may open new interventions in various tumors. Clinical trials in conjunction with standard therapies are required to explore and validate the actual potential of T. chebula and chebulinic acid respectively.

[1]
Gupta AK, Tandon N, Sharma M. Quality standards of indian medicinal plant. Indian Council Med Res 2003; 1: 207-9.
[2]
The Ayurvedic Pharmacopoeia of India; Government of india ministry of health and family welfare department of indian system of medicine & homoeopathy. 2001. Available from: https://cdn.ayush.gov.in/wp-content/uploads/2021/03/Ayurvedic-P harmacopoeia-of-India-part-1-volume-IX.pdf
[3]
Sukhdev SH, Deepak M, Joseph GVR, Joseph S, Nagar G. Indian herbal pharmacopoeia. In: Jammu Tawi: IDM, Mumbai and RRL. CSIR 1999; 2: pp. 154-9.
[4]
Bag A, Bhattacharyya SK, Chattopadhyay RR. The development of Terminalia chebula Retz. (Combretaceae) in clinical research. Asian Pac J Trop Biomed 2013; 3(3): 244-52.
[http://dx.doi.org/10.1016/S2221-1691(13)60059-3] [PMID: 23620847]
[5]
Upadhyay A, Agrahari P, Singh DK. A review on the pharmacological aspects of Terminalia chebula. Int J Pharmacol 2014; 10(6): 289-98.
[http://dx.doi.org/10.3923/ijp.2014.289.298]
[6]
A dictionary of indian raw materials and industrial products; publications and information directorate, Council of Scientific and Industrial Research. 2002. Available from: https://pdfs.semanticscholar.org/2ee1/6cb9f37a16f48f88a77d95892e8a789344f8.pdf
[7]
Aslokar LV, Kakkar KK, Chakre OJ. Glossary of indian medicinal plants with active principles; Publications and information’s directorate. Council of scientific and industrial research 1992.
[8]
Saleem A, Husheem M, Härkönen P, Pihlaja K. Inhibition of cancer cell growth by crude extract and the phenolics of Terminalia chebula retz. fruit. J Ethnopharmacol 2002; 81(3): 327-36.
[http://dx.doi.org/10.1016/S0378-8741(02)00099-5] [PMID: 12127233]
[9]
Reddy DB, Reddy TCM, Jyotsna G, et al. Chebulagic acid, a COX-LOX dual inhibitor isolated from the fruits of Terminalia chebula Retz., induces apoptosis in COLO-205 cell line. J Ethnopharmacol 2009; 124(3): 506-12.
[http://dx.doi.org/10.1016/j.jep.2009.05.022] [PMID: 19481594]
[10]
Sabu MC, Kuttan R. Anti-diabetic activity of medicinal plants and its relationship with their antioxidant property. J Ethnopharmacol 2002; 81(2): 155-60.
[http://dx.doi.org/10.1016/S0378-8741(02)00034-X] [PMID: 12065146]
[11]
Saleem A, Ahotupa M, Pihlaja K. Total phenolics concentration and antioxidant potential of extracts of medicinal plants of Pakistan. Z Naturforsch C J Biosci 2001; 56(11-12): 973-8.
[http://dx.doi.org/10.1515/znc-2001-11-1211] [PMID: 11837686]
[12]
Shin TY, Jeong HJ, Kim DK, et al. Inhibitory action of water soluble fraction of Terminalia chebula on systemic and local anaphylaxis. J Ethnopharmacol 2001; 74(2): 133-40.
[http://dx.doi.org/10.1016/S0378-8741(00)00360-3] [PMID: 11167031]
[13]
Savitha T. Antimicrobial evaluation of Terminalia chebula retz. Int J Pharm Biol Arch 2013; 4(2)
[14]
Suryaprakash DV, Sreesatya N, Avanigadda S, Vangalapati M. Pharmacological review on Terminalia chebula. Int J Res Pharm Biomed Sci 2012; 3(2): 679-83.
[15]
Mishra V, Agrawal M, Onasanwo SA, et al. Anti-secretory and cyto-protective effects of chebulinic acid isolated from the fruits of Terminalia chebula on gastric ulcers. Phytomedicine 2013; 20(6): 506-11.
[http://dx.doi.org/10.1016/j.phymed.2013.01.002] [PMID: 23462212]
[16]
Chang F, Steelman LS, Lee JT, et al. Signal transduction mediated by the Ras/Raf/MEK/ERK pathway from cytokine receptors to transcription factors: Potential targeting for therapeutic intervention. Leukemia 2003; 17(7): 1263-93.
[http://dx.doi.org/10.1038/sj.leu.2402945] [PMID: 12835716]
[17]
Santarpia L, Lippman SM, El-Naggar AK. Targeting the MAPKRASRAF signaling pathway in cancer therapy. Expert Opin Ther Targets 2012; 16(1): 103-19.
[http://dx.doi.org/10.1517/14728222.2011.645805] [PMID: 22239440]
[18]
Torres F, Quintana J, Díaz JG, Carmona AJ, Estévez F. Trifolin acetate-induced cell death in human leukemia cells is dependent on caspase-6 and activates the MAPK pathway. Apoptosis 2008; 13(5): 716-28.
[http://dx.doi.org/10.1007/s10495-008-0202-0] [PMID: 18392682]
[19]
Jin JO, Song MG, Kim YN, Park JI, Kwak JY. The mechanism of fucoidan-induced apoptosis in leukemic cells: Involvement of ERK1/2, JNK, glutathione, and nitric oxide. Mol Carcinog 2010; 49(8): n/a.
[http://dx.doi.org/10.1002/mc.20654] [PMID: 20572161]
[20]
Chang H, Lin H, Yi L, et al. 3,6-Dihydroxyflavone induces apoptosis in leukemia HL-60 cell via reactive oxygen species-mediated p38 MAPK/JNK pathway. Eur J Pharmacol 2010; 648(1-3): 31-8.
[http://dx.doi.org/10.1016/j.ejphar.2010.08.020] [PMID: 20840847]
[21]
Yang CW, Chang CL, Lee HC, Chi CW, Pan JP, Yang WC. Curcumin induces the apoptosis of human monocytic leukemia THP-1 cells via the activation of JNK/ERK Pathways. BMC Complement Altern Med 2012; 12(1): 22.
[http://dx.doi.org/10.1186/1472-6882-12-22] [PMID: 22443687]
[22]
Sanyasi S G M V, Kalidindi R. Terminalia chebula compositions and method of extracting same. CA2870159A1, 2013.
[23]
Yulin L. Preparation method of three chemical reference substances chebulinic acid, chebuligic acid and ellagic acid in terminaliachebula medicine. CN105949252A, 2019.
[24]
Lee HS, Jung SH, Yun BS, Lee KW. Isolation of chebulic acid from Terminalia chebula Retz. and its antioxidant effect in isolated rat hepatocytes. Arch Toxicol 2007; 81(3): 211-8.
[http://dx.doi.org/10.1007/s00204-006-0139-4] [PMID: 16932919]
[25]
Schmidt OTH, Hensler RH, Stephan P. über natürliche Gerbstoffe XXVI. Neochebulagsäure. Justus Liebigs Ann Chem 1957; 609(1): 186-91.
[http://dx.doi.org/10.1002/jlac.19576090117]
[26]
Schmidt OTH, Demmler K, Bittermann H, Stephan P. über natürliche Gerbstoffe XXVII. Neochebulinsäure und 1.3.6-trigalloyl-glucose. Justus Liebigs Ann Chem 1957; 609(1): 192-9.
[http://dx.doi.org/10.1002/jlac.19576090118]
[27]
Haslam E, Uddin M. Gallotannis. Part XV. Some observations on the structure of chebulinic acid and its derivatives. J Chem Soc C 1967; 2381-4.
[http://dx.doi.org/10.1039/j39670002381]
[28]
Yoshida T, Fujii R, Okuda T. Revised structures of chebulinic acid and chebulagic acid. Chem Pharm Bull 1980; 28(12): 3713-5.
[http://dx.doi.org/10.1248/cpb.28.3713]
[29]
Schmidt OTH, Klinger G, Xxviii ÜNG. über natürliche gerbstoffe XXVIII. Synthese Der 1.3.6-Trigalloyl-Glucose. Justus Liebigs Ann Chem 1957; 609(1): 199-208.
[http://dx.doi.org/10.1002/jlac.19576090119]
[30]
Schmidt OT, Mayer WD. Constitution of the fission acid C14H12O11 from chebulic and chebulagic acid. Justus Liebigs Ann Chem 1951; 571(1): 1-15.
[http://dx.doi.org/10.1002/jlac.19515710102]
[31]
Schmidt OT, Schulz J, Fiesser H, Xxviii ÜN. GAbout natural tanning agents, XXXVIII. The tannins of the myrobalans. Justus Liebigs Ann Chem 1967; 706(1): 187-97.
[http://dx.doi.org/10.1002/jlac.19677060119]
[32]
Dhingra AK, Chopra B, Grewal AS, Guarve K. Pharmacological properties of Chebulinic acid and related ellagitannins from nature: An emerging contemporary bioactive entity. Pharmacol Res - Mod Chinese Med 2022; 5: 100163.
[http://dx.doi.org/10.1016/j.prmcm.2022.100163]
[33]
Han Q, Song J, Qiao C, Wong L, Xu H. Preparative isolation of hydrolysable tannins chebulagic acid and chebulinic acid fromTerminalia chebula by high-speed counter-current chromatography. J Sep Sci 2006; 29(11): 1653-7.
[http://dx.doi.org/10.1002/jssc.200600089] [PMID: 16922284]
[34]
Yang X, Shen C, Li H, et al. Combined chromatographic strategy based on macroporous resin, high speed counter current chromatography and preparative HPLC for systematic separation of seven antioxidants from the fruit of Terminalia billerica. J Sep Sci 2019; 42(20): 3191-9.
[http://dx.doi.org/10.1002/jssc.201900356] [PMID: 31444948]
[35]
Zou D, Chen T, Li H, Chen C, Zhao J, Li Y. Separation of three phenolic high-molecular-weight compounds from the crude extract of terminalia chebula retz. by ultrasound-assisted extraction and high-speed counter-current chromatography. J Sep Sci 2016; 39(7): 1278-85.
[http://dx.doi.org/10.1002/jssc.201501358] [PMID: 26864462]
[36]
Zhang LZ, Zhao WH, Guo YJ, Tu GZ, Lin S, Xin LG. [Studies on chemical constituents in fruits of Tibetan medicine Phyllanthus emblica]. Zhongguo Zhongyao Zazhi 2003; 28(10): 940-3.
[PMID: 15620182]
[37]
Juang LJ, Sheu SJ. Chemical identification of the sources of commercial fructus chebulae. Phytochem Anal 2005; 16(4): 246-51.
[http://dx.doi.org/10.1002/pca.823] [PMID: 16042149]
[38]
Ding G, Liu Y, Wang W. [Assay of three hydrolyzable tannins in Fructus Chebulae from different habitats by RP-HPLC]. Zhong Yao Cai 2000; 23(6): 328-30.
[PMID: 12575084]
[39]
Juang LJ, Sheu SJ, Lin TC. Determination of hydrolyzable tannins in the fruit of Terminalia chebula Retz. by high-performance liquid chromatography and capillary electrophoresis. J Sep Sci 2004; 27(9): 718-24.
[http://dx.doi.org/10.1002/jssc.200401741] [PMID: 15387468]
[40]
Pellati F, Bruni R, Righi D, et al. Metabolite profiling of polyphenols in a Terminalia chebula Retzius ayurvedic decoction and evaluation of its chemopreventive activity. J Ethnopharmacol 2013; 147(2): 277-85.
[http://dx.doi.org/10.1016/j.jep.2013.02.025] [PMID: 23506992]
[41]
Pawar V, Lahorkar P, Anantha Narayana DB. Development of a RP-HPLC method for analysis of Triphala curna and its applicability to test variations in Triphala curna preparations. Indian J Pharm Sci 2009; 71(4): 382-6.
[http://dx.doi.org/10.4103/0250-474X.57286] [PMID: 20502543]
[42]
Ding G, Lu YR, Ji CR, Liu YZ. [Analysis of tannins in Fructus Chebulae and its confusion varieties by HPCE]. Yao Xue Xue Bao 2001; 36(4): 292-5.
[PMID: 12580059]
[43]
Munawar TM, Surya Prakash DV, Vangalapati M. Development of response surface methodology for optimization of parameters and quantitative analysis of chebulinic acid from composition of medicinal herbs by HPLC. Saudi J Biol Sci 2019; 26(7): 1809-14.
[http://dx.doi.org/10.1016/j.sjbs.2018.02.013] [PMID: 31762663]
[44]
Dhanani T, Shah S, Kumar S. A validated high-performance liquid chromatography method for determination of tannin-related marker constituents gallic acid, corilagin, chebulagic acid, ellagic acid and chebulinic Acid in four Terminalia species from India. J Chromatogr Sci 2015; 53(4): 625-32.
[http://dx.doi.org/10.1093/chromsci/bmu096] [PMID: 25190275]
[45]
Ravi Shankara BE, Dhananjaya BL, Ramachandra YL, et al. Evaluating the anticancer potential of ethanolic gall extract of Terminalia chebula (Gaertn.) Retz. (Combretaceae). Pharmacognosy Res 2016; 8(3): 209-12.
[http://dx.doi.org/10.4103/0974-8490.182919] [PMID: 27365992]
[46]
Maurya AP, Brahmachari S. Current status of breast cancer management in India. Indian J Surg 2021; 83(S2): 316-21.
[http://dx.doi.org/10.1007/s12262-020-02388-4]
[47]
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68(6): 394-424.
[http://dx.doi.org/10.3322/caac.21492] [PMID: 30207593]
[48]
Green M, Raina V. Epidemiology, screening and diagnosis of breast cancer in the Asia-Pacific region: Current perspectives and important considerations. Asia Pac J Clin Oncol 2008; 4 (Suppl. 3): S5-S13.
[http://dx.doi.org/10.1111/j.1743-7563.2008.00191.x]
[49]
Sharma A, Mishra T, Thacker G, Mishra M, Narender T, Trivedi AK. Chebulinic acid inhibits MDA MB 231 breast cancer metastasis and promotes cell death through down regulation of SOD1 and induction of autophagy. Cell Biol Int 2020; 44(12): 2553-69.
[http://dx.doi.org/10.1002/cbin.11463] [PMID: 32902904]
[50]
Mathiyazhagan J, Siva R, Jayaraj R, Madhyastha H, Kodiveri Muthukaliannan G. Preventive effect of combined zingiber officinale and terminalia chebula against DMBA-induced breast cancer rats via mTOR inhibition. Nutr Cancer 2022; 74(2): 687-96.
[http://dx.doi.org/10.1080/01635581.2021.1903948] [PMID: 33821702]
[51]
Mehrabani M, Jafarinejad-Farsangi S, Raeiszadeh M, et al. Effects of the ethanol and ethyl acetate extracts of Terminalia chebula retz. on proliferation, migration, and HIF-1α and CXCR-4 expression in MCF-7 cells: An in vitro study. Appl Biochem Biotechnol 2023; 195(5): 3327-44.
[http://dx.doi.org/10.1007/s12010-022-04301-z] [PMID: 36585552]
[52]
Hassan Bulbul MR, Uddin Chowdhury MN, Naima TA, et al. A comprehensive review on the diverse pharmacological perspectives of Terminalia chebula Retz. Heliyon 2022; 8(8): e10220.
[http://dx.doi.org/10.1016/j.heliyon.2022.e10220] [PMID: 36051270]
[53]
Wang M, Li Y, Hu X. Chebulinic acid derived from triphala is a promising in human colorectal carcinoma cell lines. BMC Complement Altern Med 2018; 118(1): 342.
[54]
Chhabra S, Mishra T, Kumar Y, et al. Chebulinic acid isolated from the fruits of terminalia chebula specifically induces apoptosis in acute myeloid leukemia cells. Phytother Res 2017; 31(12): 1849-57.
[http://dx.doi.org/10.1002/ptr.5927] [PMID: 28921713]
[55]
Khan MRUZ, Yanase E, Trivedi V. Extraction, phytochemical characterization and anti-cancer mechanism of Haritaki churna: An ayurvedic formulation. PLoS One 2023; 18(5): e0286274.
[http://dx.doi.org/10.1371/journal.pone.0286274] [PMID: 37256897]
[56]
Bhuvaneswarri J, Ramya V, Paddmanabhan P, Jayaraman S, Priscilla D. Effect of chebulinic acid on Bcl-2 and p53 protein expression in A431 human skin cancer cells in vitro. Drug Invent Today 2019; 11: 2640-3.
[57]
Selvaraj K, Priscilla D, Vijayalakshmi J. Chebulinic acid downregulates angiogenic markers in A431 human skin cancer cells in vitro. Drug Inven Today 2020; 13: 73-6.
[58]
Walia H, Arora S. Terminalia chebula-A pharmacognistic account. J Med Plants Res 2013; 7(78): 1351-61.
[59]
Yi ZC, Liu YZ, Li HX, et al. Tellimagrandin I enhances gap junctional communication and attenuates the tumor phenotype of human cervical carcinoma HeLa cells in vitro. Cancer Lett 2006; 242(1): 77-87.
[http://dx.doi.org/10.1016/j.canlet.2005.10.044] [PMID: 16338066]
[60]
Zheng S, Huang Y. Unveiling the anti-cancer efficiency of chebulagic acid-mediated apoptotic mechanisms in HepG2 cell line. Int J Pharmacol 2021; 17(4): 229-42.
[http://dx.doi.org/10.3923/ijp.2021.229.242]
[61]
Yoshioka K, Kataoka T, Hayashi T, Hasegawa M, Ishi Y, Hibasami H. Induction of apoptosis by gallic acid in human stomach cancer KATO III and colon adenocarcinoma COLO 205 cell lines. Oncol Rep 2000; 7(6): 1221-3.
[http://dx.doi.org/10.3892/or.7.6.1221] [PMID: 11032918]
[62]
Lee SH, Ryu SY, Choi SU, et al. Hydrolysable tannins and related compound having cytotoxic activity from the fruits of Terminalia chebula. Arch Pharm Res 1995; 18(2): 118-20.
[http://dx.doi.org/10.1007/BF02979144]
[63]
Wani K, Shah N, Prabhune A, Jadhav A, Ranjekar P, Kaul-Ghanekar R. Evaluating the anticancer activity and nanoparticulate nature of homeopathic preparations of Terminalia chebula. Homeopathy 2016; 105(4): 318-26.
[http://dx.doi.org/10.1016/j.homp.2016.02.004] [PMID: 27914571]
[64]
Kumar N, D G, Gupta G, Karnati R. Chebulagic acid from Terminalia chebula causes G1 arrest, inhibits NFκB and induces apoptosis in retinoblastoma cells. BMC Complement Altern Med 2014; 14(1): 319-9.
[http://dx.doi.org/10.1186/1472-6882-14-319]
[65]
Reddy MM, Dhas Devavaram J, Dhas J, Adeghate E, Starling Emerald B. Anti-hyperlipidemic effect of methanol bark extract of Terminalia chebula in male albino Wistar rats. Pharm Biol 2015; 53(8): 1133-40.
[http://dx.doi.org/10.3109/13880209.2014.962058] [PMID: 25625850]
[66]
Shendge AK, Sarkar R, Mandal N. Potent anti inflammatory Terminalia chebula fruit showed in vitro anticancer activity on lung and breast carcinoma cells through the regulation of Bax/Bcl 2 and caspase cascade pathways. J Food Biochem 2020; 44(12): e13521.
[http://dx.doi.org/10.1111/jfbc.13521] [PMID: 33043490]
[67]
Yi Y, Wang C, Li H, et al. Effects of chebulinic acid on differentiation of human leukemia K562 cells. Acta Pharmacol Sin 2004; 25(2): 231-8.
[68]
Kar I, Chattopadhyaya R. Effect of seven Indian plant extracts on Fenton reaction-mediated damage to DNA constituents. J Biomol Struct Dyn 2017; 35(14): 2997-3011.
[http://dx.doi.org/10.1080/07391102.2016.1244493] [PMID: 27691720]
[69]
Lal UR, Tripathi SM, Jachak SM, Bhutan KK, Singh IP. Chemical changes during fermentation of abhayarishta and its standardization by HPLC-DAD. Nat Prod Commun 2010; 5(4): 1934578X 1000500.
[http://dx.doi.org/10.1177/1934578X1000500417] [PMID: 20433076]
[70]
Aamir K, Sugumar V, Khan HU, et al. Non-toxic nature of chebulinic acid on biochemical, hematological and histopathological analysis in normal Sprague Dawley rats. Toxicol Res 2022; 38(2): 159-74.
[http://dx.doi.org/10.1007/s43188-021-00092-3] [PMID: 35419271]
[71]
Lu K, Iwenofu OH, Mitra R, Mo X, Dasgupta PS, Basu S. Chebulinic acid is a safe and effective antiangiogenic agent in collagen induced arthritis in mice. Arthritis Res Ther 2020; 22(1): 273.
[http://dx.doi.org/10.1186/s13075-020-02370-1] [PMID: 33225986]
[72]
Panunto W, Jaijoy K, Lerdvuthisopon N, et al. Acute and chronic toxicity studies ofthe water extract from dried fruits of Terminalia chebula rezt. in rats. Int J Appl Res Nat Prod 2010; 3(4): 36-43.
[73]
Kim J, Koo Y, Hong CO, Yang SY, Jun W, Lee KW. Mutagenicity and oral toxicity studies of Terminalia chebula. Phytother Res 2012; 26(1): 39-47.
[http://dx.doi.org/10.1002/ptr.3504] [PMID: 21538627]
[74]
Rathore H. A study on the cytological effects of myrobalan (Fruit of Terminalia chebula) in allium tests, ethnobot. Leafl 2006; 2006(1): 9.

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